Five investigators seek program support for structural studies of macromolecules and molecular interactions related to the etiology and control of AIDS. The program has three main objectives: 1. Determination of molecular structures (Eiserling/Eisenberg/Dickerson/Rees). To provide the fundamental structural information needed for rational drug design, structures will be determined for: the HIV envelope glycoprotein and its complexes with monoclonal antibodies and the T4 (CD4) lymphocyte receptor (Eiserling/Eisenberg/Rees), and the HIV reverse transcriptase (Dickerson). Biological materials will be supplied from the laboratories of Dr. L. Lasky (Genentech) and Dr. L. Hood (Caltech). To insure the availability of crystalline specimens for structural studies, the Core facilities for cystallization and coordinated electron microscopy and diffraction will be enhanced. To permit more rapid collection of x-ray data, diffraction equipment will be improved. 2. Molecular recognition and drug design (Dickerson/Sigman/Eisenberg/Rees). Principles of DNA-drug interactions will be developed (Dickerson). Designs for sequence-specific DNA-cutting orthophenanthrolines will be extended and applied to HIV (Sigman). Characterizations of molecular surfaces by their atomic solvation parameters and surface roughness will be extended and applied to drug binding (Rees/Eisenberg). To assure biological relevance of the work, the following scientists have agreed to consult or to collaborate as the work proceeds: Dr. James Paulson (UCLA; glycoproteins); Dr. L. Lasky (Genentech; HIV genes and proteins); Dr. L. Hood (Caltech; proteins of the immune system); Dr. O. Witte and Dr. R. Gaynor (UCLA; virology); Dr. J. Feigon (UCLA; NMR and intermolecular interactions). To permit increased emphasis on characterization of interactions and drug design, facilities for computation and graphics will be improved. 3. Training (Core and all five principal laboratories). A major effort will be undertaken to provide training in principles and practice of structural determination and molecular interactions for graduate students and postdoctorals. Three one quarter graduate courses are currently offered (by the five investigators) that provide fundamentals of biological structure and interactions.